2. The need to communicate David Taylor

3. To communicate with me The Reverend Dr David CM Taylor Reader in Medical Education Cedar House 4:27 dcmt@liv.ac.uk http://www.liv.ac.uk/~dcmt

4. To start with the obvious We are made up of cells But they clearly stick together and work together In the next couple of lectures we will start to explore the mechanisms they use.

5. Cell differentiation There are many types of cell They all start out as stem cells And differentiate into cells with different and specific functions.

6. Cell differentiation continued… In almost all cases the cells continue to do what they are supposed to do And stay in the place that they are supposed to be in One of the really big questions is how they “know” what they should do

7. Short answer The short answer is that they communicate with each other But how? I recommend Medical Sciences by Naish, Revest and Court (2009) but there is a 2014 edition published by Saunders. This lecture uses chapters 2 and 10

8. First Remember what the membrane looks like Fig 2.28 in Naish 1 st edition

9. Direct communication Tight junction prevents Desmosome joins Gap junction communicates Fig 2.29 in Naish 1 st edition

10. Tight junctions Form a belt around the cell, anchoring it to neighbouring cells. NOT attached to the cytoskeleton The belt stops membrane proteins moving past it. And stops molecules diffusing across the tissue

11. Desmosomes Anchor cells together ARE attached to cytoskeleton Cadherins form the links between the “plaques” in the individual cells

12. Gap Junctions Are channels or bridges between cells formed from connexins. They allow small molecules and ions to pass between cells. So small chemical and electrical signals can pass through them. This is how electrical signals pass through smooth muscle.

13. Chemical communication A chemical is released which binds to a receptor on a cell membrane (or sometimes inside the cell). The chemical may travel a very short distance, or a long distance.

14. Paracrine and Autocrine Paracrine Autocrine

15. examples Paracrine Nitric Oxide Local vasodilator released from endothelial cells Autocrine Prostaglandins Inflammatory mediators

16. Neural and endocrine Neural Endocrine Electrical signal Hormone neurotransmitter Blood

17. Neural examples Neural Glutamate excitatory in CNS Acetylcholine Excites skeletal muscle Noradrenaline Causes vasoconstriction

18. Hormones The chemical type usually reflects the way that they act on the target tissues Amino acid derivatives Steroids Peptides Proteins Glycoproteins

19. Amino acid derivatives Adrenaline and noradrenaline “catecholamines”, circulate free or weakly bound to albumin, short half-life. Bind to G-protein coupled receptors Thyroid hormones (T3 and T4) Circulate bound to plasma proteins. Long half lives. Transported through membranes and bind to nuclear receptors

20. Steroids Oestrogens, androgens aldosterone etc., Circulate bound to plasma proteins, but readily diffuse through cell membrane. Bind to intracellular steroid receptors Figure 10.1 from Naish 1 st Edition

21. Peptides etc., Peptides, proteins and glycoproteins Are usually carved from prohormones when needed Then are secreted by exocytosis And do not usually bind to plasma proteins. They are very different in structure so their effects are mediated by several different mechanisms (see next lecture)

22. Peptides Thyrotropin releasing factor (TRH) Gonadotrophin releasing hormone (GnRH) Adrenocorticotropic hormone (ACTH) Antidiuretic hormone (ADH, Vasopressin) Oxytocin Glucagon Somatostatin Vasoactive intestinal polypeptide (VIP)

23. Proteins Insulin Insulin-like growth factors (IGFs) Growth Hormone (GH) Prolactin (PRL) Placental Lactogen(PL) Parathyroid hormone (PTH)

24. Glycoproteins Proteins which are glycosylated Thyroid Stimulating Hormone (TSH) Follicle stimulating hormone (FSH) Luteinising Hormone (LH) Chorionic gonadotrophin (hCG)

25. This year You will be looking at the way: Insulin, glucagon, grehlin, leptin etc control glucose, lipids and metabolism The renin-angiotensin/aldosterone system controls blood pressure Hormones control reproduction And probably many other examples, which show the importance of hormones in normal life and development.

26. Ligand/receptor The molecule that is the signal is called a ligand. It binds to a receptor which triggers the effect. There are several types of receptor, and we will focus on the main ones.

27. G-protein coupled receptors Membrane bound Activate other intracellular signalling processes through “second messengers” Chapter 4 in Naish (2009 edition) is excellent, but don’t expect to understand it all at this stage!

28. G-proteins G s stimulates adenylate cyclase G i inhibits adenylate cyclase G q Activates phospholipase C β GsGs GTP β γ Ligand Receptor membrane

29. cAMP as second messenger γ β G γ β G Adenylate cyclase ATP cAMP AMP Inactive PKAActive Protein kinase A ProteinProtein-phosphate + - phosphodiesterase Ligand ALigand B GTP

30. Receptor tyrosine kinases Receptor tyrosine kinase is a transmembrane protein which is normally inactive. When the ligand binds (e.g. insulin), the receptor subunits aggregate, and the tyrosine molecules become phosphorylated other intracellular proteins then bind to the tyrosine kinase and are activated

31. Nuclear receptors Hormones like the steroid hormones are lipid soluble and can diffuse through the plasma membrane. Inside the cell they bind to their receptors, causing a conformational change. The conformational change allows a dimer to form The dimer binds to recognition sites on DNA and triggers (or sometimes inhibits) transcription of specific genes

32. Ligand gated channels A simple example is the acetylcholine receptor in muscle Acetylcholine binds to a receptor which opens a channel to allow Na + into the cell The influx of Na + depolarises the cell The depolarisation causes the release of intracellular Ca 2+ Which allows the actin and myosin to bind together, and contraction to occur.

33. Resting Membrane Potential Cells in the body are mostly impermeable to Na + and mostly permeable to K + and Cl - Intracellular proteins are negatively charged and can’t leave the cell. When the cell is “at rest” the membrane potential is a compromise between the charge carried by the diffusible ions, and the concentration gradient for each ion Normally this is about -90mV, or -70mV in excitable cells

34. The action potential e.g. in neurones -70 mV -55mV +40mV Fully permeable to Na +(+40mV) Fully permeable to K + (-90mV) 1mS Resting membrane potential (-70mV)

35. The action potential e.g. in neurones -70 mV -55mV +40mV VANC open VANC close Fully permeable to Na +(+40mV) Fully permeable to K + (-90mV) 1mS stimulus Resting membrane potential (-70mV)

36. The action potential -70 mV -55mV +40mV VANC open VANC close Fully permeable to Na +(+40mV) Fully permeable to K + (-90mV) 1mS stimulus Resting membrane potential (-70mV) gNa + gK +

37. The wave of depolarisation ---------- ++++++++++ +-+------- --++++++++ -+-+------ ++ - -++++++

38. The synapse Figure 8.22 from Naish (2009)

39. At the synapse In response to depolarisation Voltage-dependent Ca 2+ channels open Which allows vesicles containing neurotransmitters to fuse with the membrane The neurotransmitter crosses the synaptic cleft And binds to receptors…..